Terbinafine, or (E)-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methyl-1-naphthalenemethanamine, is a known medicament with antifungal activity for topical use and has been first disclosed in EP 024587. The (E) stereoisomer of said compound is biologically active. In view of the interest of this product, various alternative processes for its production, more advantageous than those disclosed in EP 024587, have been developed, particularly those disclosed in EP 421302, WO 02/02503 and EP 1236709.
EP 421302 and WO 02/02503 disclose processes in which the last synthetic step comprises the reaction of N-(3-chloro-2-propenyl)-N-methyl-1-naphthalenemethanamine with tert-butylacetylene, in the presence of an organic amine and catalytic amounts of palladium salts and copper(I) iodide. Palladium compounds conventionally used for the coupling reaction known as “palladium catalyst-cross coupling reaction” are used as palladium catalysts. Examples of the palladium compounds reported in EP 421302 and WO 02/02503 comprise palladium-tertiary phosphine complexes, combinations of a palladium salt with a tertiary phosphine and a combination of a palladium complex with a tertiary phosphine. The processes described in said documents afford terbinafine in good yields but they have some remarkable drawbacks: for instance, the final product is contaminated by palladium and decomposition products of the palladium-phosphorous complexes, which have to be removed with cumbersome, expensive purification processes, for example by liquid column chromatography.
The process disclosed in EP 1236709 has overcome the drawbacks connected with the use of palladium catalysts, by reacting N-(3-chloro-2-propenyl) -N-methyl-1-naphthalenemethanamine with tert-butylacetylene in alkali medium in the presence of copper(I) salts only. This process affords terbinafine free from catalyst contaminations in good yield, but it requires long reaction times, which do not suitably meet the requirements for the industrial production on a large scale.
As a consequence, there is the need for alternative processes for the preparation of terbinafine on an industrial scale, which overcome the drawbacks of the known processes.
The inventors of the present invention have surprisingly found a novel process for the preparation of terbinafine, which can be carried out in comparatively short reaction times and affords a product free from catalyst contaminations and other reaction by-products, and moreover in significantly quantitative yield and improved stereoisomeric (E/Z) ratio.